This investigation deals with the metabolism of cholestanol, cholesterol, and bile acids in patients with cerebrotendinous xanthomatosis (CTX), gallstones, and arteriosclerosis. Specifically we propose to investigate (1) the biochemical defect in cerebrotendinous xanthomatosis. Since measurements of bile acid synthesis in patients with this disease is subnormal, the defect in the bile acid synthetic pathway is suspected as the major defect. We will explore the mechanism of bile acid synthesis in CTX; seek to isolate and identify bile acid intermediates, measure quantitatively the output of these precursors in bile and feces, define the specific hepatic enzymatic defect, and determine if any bile acid intermediates are converted to cholestanol which accumulates in extraordinary quantities in CTX. Also we will examine the effect of bile acid feeding on the regulation of bile acid synthesis and the excretion of precursors in CTX. (2) The quantitative significance of cholestanol will be determined in patients with gallstones and arteriosclerosis. Measurements of cholestanol production and pool size will be obtained by isotope kinetic techniques and will be compared with similar values derived from normal individuals. (3) The cholestanol biosynthetic pathway will be explored. The identification of key intermediates and the biosynthetic sequence will be determined. The tissue site of synthesis will be identified and factors governing feed-back regulation elucidated. (4) The elucidation of the cholesterol biosynthetic pathway in CTX. Since many cholesterol precursors are secreted in the bile and feces of CTX subjects, we will isolate and identify these intermediates, define the proper cholesterol biosynthetic sequence, determine the factors regulating cholesterol synthesis and examine feedback regulations in the CTX subjects with the objectives of expanding these observations in subjects with gallstones and arteriosclerosis.